Project Summary Back pain is the most common cause of disability worldwide with a lifetime prevalence of 80%. Intervertebral disc (IVD) degeneration is a major cause of low back pain. Currently, IVD degeneration is treated only symptomatically. Our ability to effectively treat disc disease is largely hampered by 1) an incomplete understanding of the biological processes of IVD development, function and disease; 2) The lack of an efficient and streamlined protocol for new drug discovery due to limited research platforms. To address the aforementioned problems, we propose to develop a novel microfluidic ?disc-on-a-chip? organ culture platform tailored for mouse IVD. Our application-oriented microfluidic devices are designed to address key pathogenic factors, including biochemical (e.g. nutrients and inflammatory cytokines), mechanical and genetic aspects, contributing to disc degenerative diseases. Our short-term objective is to develop proof- of-concept microfluidic devices tailored for mouse IVD culture in multi-throughput (Aim 1) and physiologically simulated (Aim 2) manners and demonstrate respective application-oriented strategies for bridging in vitro IVD culture methodology with in vivo IVD biology/pathology and simulated drug evaluation. Our long-term goal is to establish a streamlined drug discovery protocol for new therapeutic and regenerative strategies using our integrated microfluidic mouse IVD culture platform. Microfluidic devices have been proven to be advantageous over their conventional counterparts in many aspects, since miniaturization, automation, and integration of fluidic control systems allow smaller reagent consumption, lower cost, shorter turnaround time, and higher throughput. Our proposed microfluidic mouse IVD culture devices will not only fill in the methodological blank of ?disc-on-a-chip?, but also demonstrate a number of revolutionary benefits along the road to tackle disc degeneration: a) Culture media is continuously supplied/refreshed to mimick in vivo blood circulation, providing a unique platform to study the impacts of various biochemical factors such as oxygen, nutrients, cytokines, and growth factors on IVD metabolism; b) With multi- throughput platform, we can easily culture dozens of IVD samples, benefiting expedited drug discovery and evaluation protocols within a precisely defined microenvironment (Aim 1); c) Our physiologically simulated mechanical loading on mouse IVD empowers otherwise impossible cross-talking studies between genetic factor and mechanical stress (Aim 2); and d) Our micro-scale ?disc-on-a-chip? device can be customized, commercialized, manufactured in mass production, and utilized by all research laboratories, shifting the paradigm of conventional disc research and meanwhile accelerating drug discovery processes in the battle against disc degeneration.